Novel 3-sulphonamido-quinazolin-4(3H)-one derivatives: microwave-assisted synthesis and evaluation of antiviral activities against respiratory and biodefense viruses.

We designed and synthesized novel 2,3-disubstituted quinazolin-4(3H)-ones by microwave technique and characterized them by spectral analysis. Synthesized compounds were screened for cytotoxicity and for antiviral activity against influenza A (H1N1, H3N2 and H5N1), severe acute respiratory syndrome corona, dengue, yellow fever, Venezuelan equine encephalitis (VEE), Rift Valley fever, and Tacaribe viruses in cell culture. A neutral red uptake assay was used to determine 50% virus-inhibitory concentrations (EC50) of test compounds and their 50% cytotoxicity concentration (CC50) in uninfected Madin-Darby canine kidney, Vero, and Vero 76 cells; selectivity indices (ratio of CC50 to EC50) were derived from the data. The compound 4-(6,8-dibromo-4-oxo-2-phenyl quinazolin-3(4H)-yl)-N-(4,5-dimethyloxazol-2yl) benzenesulphonamide 15 inhibited the replication of avian influenza (H5N1) virus (EC50 = 8.4 microg/ml, CC50 > 100 microg/ml, SI > 11.9) as did 4-(6-bromo-4oxo-2phenylquinazolin-3(4H)-yl) benzene]sulphonamide 5 (EC50 = 3 microg/ml, CC50 = 32 microg/ml, SI = 11). Compound 5 was also moderately active against VEE and Tacaribe viruses. The methodology described in this report is applicable for rapid synthesis of many compounds with potential antiviral properties.

Short communication inhibitory activity of 4-[(1,2-dihydro-2-oxo-3H-indol-3-ylidene)amino]-N-(4,6-dimethylpyrimidin-2-yl) benzenesulphonamide and its derivatives against orthopoxvirus replication in vitro.

4-[(1,2-Dihydro-2-oxo-3H-indol-3-ylidene)amino]-N-(4,6-dimethylpyrimidin-2-yl) benzenesulphonamide and its derivatives were tested in vitro for antiviral activity against vaccinia and cowpox virus replication in human foreskin fibroblast (HFF) cells, and their activity was compared with cidofovir (CDV). Among the tested compounds, 4-[(5-methyl-1,2-dihydro-2-oxo-3-H-indol-3-ylidene)amino]-N-(4,6-dimethylpyrimidin-2-yl)benzene-sulphonamide was the most active against vaccinia virus, with a 50% effective concentration (EC50) value of 18 microM and 4-[(N-acetyl-1,2-dihydro-2-oxo-3-H-indol-3-ylidene)amino]-N-(4,6-dimethylpyrimidin-2-yl) benzenesulphonamide was the most active against cowpox virus (EC50=33 microM). Cidofovir was found to have an EC50 of 20 microM and 32 microM against vaccinia and cowpox virus, respectively. Most of the tested compounds were non-cytotoxic (>300 microM) in HFF cells as determined by a neutral red uptake assay. The substitution of a halogen atom at the 5-position of isatin abolished the antiviral activity.

Anti-influenza virus activities of 4-[(1,2-dihydro-2-oxo-3H-indol-3-ylidene)amino]-N-(4,6-dimethyl-2-pyrimidin-2-yl)benzenesulphonamide and its derivatives.

4-[(1,2-Dihydro-2-oxo-3H-indol-3-ylidene)amino]-N-(4,6-dimethyl-2-pyrimidinyl)-benzenesulphonamide (SPIII-5H) and related compounds were tested for antiviral activity against influenza A (H1N1, H3N2, and H5N1) and B viruses in Madin Darby canine kidney (MDCK) cell culture. Among the compounds tested, SPIII-5H and four derivatives (5-chloro [SPill-5Cl], 5-bromo [SPIII-5Br], 5-methyl [SPIII-5Me] and N-acetyl [SPIII-NA]) showed similar antiviral potencies, with only the 5-fluoro (SPIII-5F) derivative being ineffective. Fifty percent effective concentration (EC50) values were determined in cytopathic effect (CPE) inhibition assays quantified by neutral red dye uptake. By this method, the active compounds were inhibitory to the H1N1 strain of influenza A at 2.7-5.2 microg/ml, to the H3N2 strain of influenza A at 13.8-26.0 microg/ml, to the H5N1 strain of influenza A at 3.1-6.3 microg/ml and to influenza B at 7.7-11.5 microg/ml. Confirmatory virus yield reduction studies against influenza A (H1N1) virus demonstrated antiviral activity (90% inhibition) at concentrations of 2-10 microg/ml. No cytotoxic effects were evident in actively growing uninfected cells or stationary monolayers at 100 microg/ml. Potencies of the compounds were similar to those of ribavirin, but much less than those of oseltamivir carboxylate against the various viruses. Time-of-addition studies indicated the compounds inhibited an early step in the virus replication cycle, probably virus adsorption/penetration, and no virucidal activity was evident. The basic molecule is amenable to diverse chemical modifications, which may improve water solubility and antiviral potency.

Activity of isatine-sulfadimidine derivatives against 2009 pandemic H1N1 influenza virus in cell culture.

BACKGROUND: The development of antiviral drugs has provided crucial new means to mitigate or relieve the debilitating effects of many viral pathogens. New classes of inhibitors are essential to combat swine influenza viral infection. METHODS: A series of isatine-sulfadimidine derivatives were screened for antiviral activity against swine influenza A/California/07/2009 (H1N1) virus in Madin-Darby canine kidney (MDCK) cell culture. Cytotoxicity of the synthesized compounds was also tested in uninfected MDCK cells. RESULTS: All the compounds inhibit the influenza A (H1N1) in MDCK cells. The most active compounds, SPIII-5Br and SPIII-5H, inhibited virus-induced cytopathology by 50% at 27 and 30 microM, respectively, with 50% cytotoxicity occurring at a much higher dose (975-1,000 microM). The positive control compound ribavirin inhibits the replication of the virus at 18 microM and cytotoxic concentration was found to be >1,000 microM. CONCLUSIONS: SPIII-5Br and SPIII-5H exhibited potency in the same range as ribavirin and are suitable candidate molecules for further investigation.